Components of
Participating OrganizationsThis FOA is developed as part of the
NIH-wide Genes, Environment, and Health Initiative (GEI). All NIH Institutes
and Centers participate in NIH-wide initiatives.
This FOA will be administered by NIDA (http://www.nida.nih.gov) on behalf of the NIH (http://www.nih.gov)

NOTICE: Applications submitted in response to this
Funding Opportunity Announcement (FOA) for Federal assistance must be submitted
electronically through Grants.gov (http://www.grants.gov) using the SF424 Research and Related (R&R) forms and the SF424
(R&R) Application Guide.

APPLICATIONS MAY NOT
BE SUBMITTED IN PAPER FORMAT.

This FOA must be read
in conjunction with the application guidelines included with this announcement
in Grants.gov/Apply
for Grants (hereafter called Grants.gov/Apply).

A registration process
is necessary before submission and applicants are highly encouraged to start
the process at least four (4) weeks prior to the grant submission date. See Section IV.

Purpose. The
National Institute on Drug Abuse on behalf of
the NIH Genes, Environment and Health Initiative encourages functional
characterization of genetic variants that have been statistically
nominated to be associated with a particular outcome through common,
complex disease gene discovery approaches, such
as genome-wide association studies, candidate gene approaches, or
sequencing studies. This FOA supports research relating genetic variation
to biological mechanism, or disease causality. Areas of interest include,
but are not limited to, relatively low
throughput approaches (e.g. transgenic mouse approaches) to test some of
the most promising variants for changes in function; or exploit
high-throughput tests (e.g. yeast, C. elegans, cell culture systems, or
computational approaches) to look at different
aspects of variant function.

Mechanism of Support. This FOA will utilize the R03 grant
mechanism and runs in parallel with a FOA of
identical scientific scope, RFA-DA-09-003,that
solicits applications under the R21 grant
mechanism.

Funds
Available and Anticipated Number of Awards.The NIH
has committed $5 million total costs in FY 2009 ($10 million over the
total project period of two years) to fund applications in response to
RFA-DA-09-003 and RFA-DA-09-004. Approximately 10 awards are anticipated
for this FOA.

Budget and Project Period. Budgets
for direct costs of up to $100,000 per year and a project duration of up
to two years may be requested for a maximum of $200,000 direct costs over
a two-year project period.

Research
Plan Component Length: Items 2-5 of the PHS398 Research Plan
component of the R03 application may not exceed 10 pages, including
tables, graphs, figures, diagrams, and charts. See http://grants.nih.gov/grants/funding/funding_program.htm

Eligible Project
Directors/Principal Investigators (PDs/PIs). Individuals
with the skills, knowledge, and resources necessary to carry out the
proposed research are invited to work with their institution/ organization
to develop an application for support. Individuals from underrepresented
racial and ethnic groups as well as individuals with disabilities are
always encouraged to apply for NIH support.

Number of PDs/PIs. More than one PD/PI (i.e., multiple PDs/PIs) may be designated on the
application.

Number of Applications. Applicants
may submit more than one application, provided each application is
scientifically distinct.

Resubmissions. Resubmission applications are not permitted in
response to this FOA.

Renewals.Renewal
applications are not permitted in response to this FOA

Genome-wide association studies (GWAS) are producing a large
number of potentially important gene variants and potentially important to
common diseases. Understanding the function of these associated gene variants,
and the mechanisms of how they contribute to and/or cause disease is an obvious
next step towards realizing how best to relate the genomic data learned from
GWAS to public health. Measuring the discrete contribution of a particular
variant or environmental factor to the condition, and being able to assess the
interplay together or in combination with other alleles/environmental factors
is an integral component of the NIH Genes, Environment, and Health Initiative
(GEI). Determining the functional relevance of the genetic variant(s) is the
purpose of this funding opportunity announcement (FOA). This FOA focuses
solely on functional characterization of gene variants which are strongly
suggested to be associated with common, complex human diseases and identified
through candidate gene, GWAS, and other approaches.

There is a companion announcement to this FOA, using the R21
mechanism (RFA-DA-09-003),
focused on projects that are more innovative in nature and may not have
preliminary data.

The Genes and Environment Initiative (GEI)

The GEI is a four-year, NIH-wide program to support efforts to identify major
genetic susceptibility factors for diseases of substantial public health impact
and to develop technologies for reliable and reproducible measurement of
environmental exposures that interact with genetic susceptibility to influence
health and disease. It is being coordinated and implemented by an NIH-wide GEI
Coordinating Committee, administratively led by the National Human Genome
Research Institute (NHGRI) and the National Institute of Environmental Health
Sciences (NIEHS).

GEI is intended to be a
multi-component program involving several related solicitations (http://www.gei.nih.gov/genetics/funding.asp).
A major component supports genome-wide association studies (GEI-GWA), either in
an initial discovery phase (assaying single nucleotide polymorphisms, or SNPs,
to capture at least 80% of human genomic variation), or in a replication phase
(assaying a subset of the most strongly associated SNPs or other genetic
variants in one or more additional groups of subjects), as well as methods
development for GWAS. Information on other GEI genetics components
can be found at http://www.gei.nih.gov/genetics/index.asp.

Recognizing that common
diseases are likely due to factors in the physical, chemical, behavioral,
social and developmental environments interacting with genetic predisposition,
GEI also includes a substantial environmental component devoted to developing
and field testing new technologies for assessing such exposures. The potential
for applying these technologies (particularly those suitable for use on stored
biospecimens) in population samples selected through GEI for genetic studies
will also be examined. Information about opther GEI exposure biology components
can be found at http://www.gei.nih.gov/exposurebiology/.
The value of the existing epidemiologic and genotyping data for investigation
of gene-environment interactions will be increased substantially by
understanding and characterizing functional mechanisms caused by the genetic
variants that are identified through GWAS. To ensure that the maximal
scientific benefit is derived from this significant public investment, the
mechanisms identified, phenotypic measures, and applicability and scalability
of the functional tests developed through this FOA will be made rapidly and
widely available for research use.

Background

One of the biggest
challenges in functional genetics is establishing that a particular SNP or gene
variant in a disease-associated region is indeed the variant contributing to,
or causing the disease. It is possible that a nominated or associated variant
is in linkage disequilibrium with another variant, which may also be associated
with the disease. Some variants associated with disease are predicted to
change conserved amino acids, are predicted to affect mRNA stability, alter
splice junctions, or may be in regulatory regions that affect the expression of
the protein. However, most variants that have been associated with a particular
disease phenotype do not have predictable effects on gene function, nor do they
differ in a known measurable function as yet.

Approaches such as
computational biology and systems biology are necessary to comprehensively
identify important alterations of normal biological pathways induced by genetic
variants, environmental stimuli, and developmental factors. The integration of
“-omics” (genomics, comparative genomics, proteomics, transcriptomics,
metabolomics, epigenomics, and informatics) with high-throughput technologies
(RNAi, tissue arrays, etc) into comprehensive pathway-driven approaches will be
necessary to understand functionally and mechanistically the role of
environment, development, and genetics in complex human diseases. Hierarchical
Bayesian computational models incorporating “-omics” and system level data will
be useful to understand the relationship of multiple pathways, with highly
correlated data, involved in complex genetic, environmental, and developmental
interactions.

Measuring the discrete
contribution of a particular variant or environmental factor to a phenotype,
and being able to assess the interplay together or in combination with other
alleles and environmental factors are integral parts of this initiative. Precise
and accurate phenotyping is critical, and differences between ancestral and
variant alleles in any of a multitude of processes could reveal how the variant
influences the terminal phenotype or the intermediate/endophenotype of the
organism. The function of a single allele within an organism may differ
depending on a variety of factors, including physical, chemical, biological,
behavioral, social, and developmental. There is a need for qualitative and
quantitative measures, and respondents should be mindful of how to define,
scale, and standardize the functional effect that defines the phenotype.

Objectives

The goal of this FOA is to
support initial studies focusing on the characterization of functional effects
of common gene variants identified through candidate gene approaches and GWAS,
and to elucidate gene x environment interactions at the functional level. The
term “gene variant” is used to apply to any type of genetic variation
identified through human candidate gene or GWAS analysis. Applications
submitted in response to this FOA may vary greatly in depth and breadth of
functional analyses. One could investigate a single high priority genetic
variant in detail (e.g. using transgenic mouse approaches), or test several
hundred genetic variants rapidly (e.g. using high throughput RNAi testing).
Model organisms and/or human studies are acceptable, as is investigation at
different levels of function, ranging from the use of standard protocols to
state-of-the-art technologies to explore cellular to physiological or
behavioral function of the whole organism.

Because of linkage
disequilibrium (LD), statistical methods will generally allow the
identification of sets of genetic variants that possibly affect function,
without allowing the identification of the specific contributing or causal
variant. Additionally, a functional effect may not manifest without
appropriate environmental or developmental triggers. Accordingly, this FOA
supports five approaches in developing a hypothesis and study plans for
investigating functional effects of genetic variants associated with complex
diseases, and nominated by candidate gene, GWAS, or other approaches: (1) Test
G only: functional characterization of the nominated variant; (2) Test G x G:
characterization of combinations of genetic variants that may be acting
additively, thus examining the discrete contributions of each variant either
singly or in combination—additive and potentially synergistic interactions
between SNPs in metabolic pathways, for example; (3) Test Gs in LD: developing
or performing high-throughput functional screens on a number of gene variants
that are in LD with a statistically nominated gene variant from an association
study to prioritize potential functional candidate alleles; (4) Test G x E, G x
D, or G x E x D: examine consequences of environmental or developmental
manipulations on an already established functional gene variant to determine
mechanism(s) of interactions, or (5) G and E: development of transforming
computational approaches that enhance the predictive ability of determining
functional effects of gene variants, for example, methods to examine testing a
genetic variant that has little or no effect until it is combined with an
environmental exposure, methods to predict G x E interactions on biological
pathways relevant to disease, methods to predict functional effects of gene
variants combined with environmental or developmental factors, or methods to
improve on G x E incorporation into computational models.,

Examples of research
projects or questions may include, but are not limited to, the following:

Studies examining systems level approaches to
understand the functional variant on gene expression, protein expression,
modifications, localization, etc. (e.g. it is possible that a molecular or environmental perturbation will trigger a cascade
of events/effects)

Evaluation of models that incorporate known functional
genetic information, as well as environmental, behavioral, and/or
developmental factors for refining phenotypes and subcategorization of complex disease (e.g. defining molecular
phenotypes based on proteomic or consistent gene expression profiling)

Development of validated functional tests to predict
phenotypes, or the development of clinical applications, using
functionally validated gene variants

Studies using transgenic assay systems in appropriate
model organisms to understand the functional significance of
environmentally relevant SNPs and other types of genetic variants (e.g
copy number variations, inversions and balanced translocations, etc)

Approaches and studies designed for SNP functional
analysis of environmentally-relevant genes

Studies measuring the
functional interplay of the GWAS nominated ancestral and variant allele
with other alleles or environmental factors

Studies utilizing knockdown or overexpression of
candidate genes with the ancestral and variant alleles in cells, tissues,
or whole organisms can be used to confirm and further characterize
candidate gene and variant function in disease. Approaches for
knockdown could include knockout and conditional knockout mutant cells or
animals, or RNAi-related knockdown strategies. Approaches for
overexpression could include transgenesis or localized overexpression
using virally-mediated strategies.

Studies measuring the effects of function of the GWAS
nominated ancestral and variant alleles within developmental stages

Studies that use protein
structure/function relationships to predict functional effects of a gene
variant

Studies utilizing large genetic reference populations
(e.g. Collaborative Cross, recombinant inbred strains) that can be used to
study the context of specific gene variants or
the combination of variants on function

A detailed justification
for the gene variant(s) to be characterized is essential and must include:

Summary of
the study (e.g. GWAS, candidate gene, QTL) identifying the gene variant as
well as the replication or validation data supporting its prioritization
for further functional analysis

Justification
of the functional characterization approach

Justification
of the environmental factor(s) proposed to examine G x E (e.g. provide evidence
that the exposure affects a given pathway), if applicable

Sensitivity
of the functional measurement (will you be successful in detecting a
functional change)

Potential
analytic interpretations of the functional effect and alternative
corrections in establishing mechanism (e.g. there may be redundancies and
compensatory mechanisms built into the system, which may need to be taken
into account)

This FOA will NOT support
sample collection, novel technology development, replication, fine-mapping, or
re-sequencing approaches. Selection criteria for funding would include
studies that provide a diversity of trait and exposure information on a
population basis. This FOA encourages studies examining the function of gene
variants common in multiple or diverse population groups, or in conditions
disproportionately affecting under-represented minorities.

As part of the GEI
initiative, applicants should request funds to attend one research meeting to
be held in conjunction with the GEI-GWA study investigators (GENEVA; http://www.genevastudy.org/), or other
GEI group). The budget for this meeting should be reflected in the second
years’ budget.

This FOA is part of the trans-NIH GEI program. Data generated by successful applicants responding to this initiative should
provide a solid foundation for a future R01 (or other appropriate NIH
mechanism) application. There is no plan for re-issuing this FOA. Therefore,
successful applicants for this FOA may wish to contact program staff at an appropriate NIH Institute/Center (IC) during their first
year of funding to determine possible interest and strategies for developing
and submitting a follow-on application to a specific IC. Although no obligation
from an individual IC exists, it is anticipated that
any future projects will be considered in the investigator-initiated
application pool by individual ICs through competitive peer review, building on
the high quality data and/or resources generated by this GEI FOA.

This FOA will use theR03 award mechanism. The Project Director/Principal
Investigator (PD/PI) will be solely responsible for planning, directing,
and executing the proposed project.

This FOA uses “Just-in-Time” information concepts (see SF424 (R&R) Application
Guide). It also uses the modular as well as the non-modular
budget formats (seehttp://grants.nih.gov/grants/funding/modular/modular.htm).
Specifically, a U.S. organization submitting an application with direct costs
in each year of $250,000 or less (excluding consortium Facilities and
Administrative [F&A] costs) must use the PHS398 Modular Budget component.

U.S. applicants requesting more than
$250,000 in annual direct costs and all Foreign applicants must complete and
submit budget requests using the Research & Related Budget component.

2.
Funds Available

The NIH intends to commit $5M (total costs), in FY2009,
to fund applications in response to the DA-09-003 (R21) and DA-09-004
(R03) announcements

Approximately ten R03 awards are anticipated.

Direct costs are limited to $100,000 per year over a
2-year period, with no more than $200,000 in direct costs allowed over the
entire two year period.

Because the
nature and scope of the proposed research will vary from application to
application, it is anticipated that the size and duration of each award will
also vary. Although the financial plans of the IC(s) provide support for this
program, awards pursuant to this funding opportunity are contingent upon the
availability of funds.

Facilities
and Administrative (F&A) costs requested by consortium participants are not
included in the direct cost limitation. See NOT-OD-05-004.

The decision of whether to
apply for a grant with a single PD/PI or multiple PDs/PIs grant is the
responsibility of the investigators and applicant organizations and should be determined
by the scientific goals of the project. Applications for grants with multiple
PDs/PIs will require additional information, as outlined in the instructions
below. The NIH review criteria for approach, investigators, and environment
have been modified to accommodate applications involving either a single PD/PI
or multiple PDs/PIs. When considering the multiple PD/PI option, please be
aware that the structure and governance of the PD/PI leadership team as well as
the knowledge, skills and experience of the individual PDs/PIs will be factored
into the assessment of the overall scientific merit of the application.
Multiple PDs/PIs on a project share the authority and responsibility for
leading and directing the project, intellectually and logistically. Each
PD/PI is responsible and accountable to the grantee organization, or, as
appropriate, to a collaborating organization, for the proper conduct of the
project or program, including the submission of required reports. For further
information on multiple PDs/PIs, please seehttp://grants.nih.gov/grants/multi_pi.

Applicants are not
permitted to submit a resubmission application in response to this FOA.

Renewal applications are not
permitted in response to this FOA.

Applicants
may submit more than one application, provided each application is
scientifically distinct.

Section IV. Application and Submission Information

To
download a SF424 (R&R) Application Package and SF424 (R&R) SBIR/STTR
Application Guide for completing the SF424 (R&R) forms for this FOA, use
the “Apply for Grant Electronically” button in this FOA or link to http://www.grants.gov/Apply/ and follow
the directions provided on that Web site.

A one-time registration is required for institutions/organizations at both:

The individual(s) designated as
PDs/PIs on the application must be registered also in the NIH eRA Commons. In the case of multiple PDs/PIs, all PDs/PIs must be registered and be assigned
the PI role in the eRA Commons prior to the submission of the application.

Each PD/PI must
hold a PD/PI account in the Commons. Applicants should not share a Commons account for both an Authorized Organization
Representative/Signing Official (AOR/SO) role and a PD/PI role; however, if they have both a
PD/PI role and an NIH Internet Assisted Review (IAR) role, both roles should
exist under one Commons account.

When multiple PDs/PIs are
proposed, all PDs/PIs at the applicant organization must be affiliated with
that organization. PDs/PIs located at another institution need not be affiliated
with the applicant organization, but must be affiliated with their own
organization to be able to access the Commons.

This registration/affiliation must
be done by the AOR/SO or his/her designee who is already registered in the Commons.

Both the PDs/PI(s) and
AOR/SO need separate accounts in the NIH eRA Commons since both are authorized
to view the application image.

Note that if a PD/PI is
also an NIH peer reviewer with an Individual DUNS and CCR registration, that
particular DUNS number and CCR registration are for the individual reviewer
only. These are different than any DUNS number and CCR registration used by an
applicant organization. Individual DUNS and CCR registration should be used
only for the purposes of personal reimbursement and should not be used on any
grant applications submitted to the Federal Government.

Several of the steps of
the registration process could take four weeks or more. Therefore, applicants
should immediately check with their business official to determine whether
their organization/institution is already registered in both Grants.gov and the Commons. The NIH will accept
electronic applications only from organizations that have completed all
necessary registrations.

1. Request Application Information

Applicants must
download the SF424 (R&R) application forms and the SF424 (R&R)
Application Guide for this FOA through Grants.gov/Apply.

Note:
Only the forms package directly attached to a specific FOA can be used. You
will not be able to use any other SF424 (R&R) forms (e.g., sample forms,
forms from another FOA), although some of the "Attachment" files may
be useable for more than one FOA.

Prepare all
applications using the SF424 (R&R) application forms and in accordance with
the SF424 (R&R) Application Guide for this FOA
through Grants.gov/Apply.

The SF424 (R&R)
Application Guide is critical to submitting a complete and accurate application
to NIH. Some fields within the SF424 (R&R) application components, although
not marked as mandatory, are required by NIH (e.g., the “Credential” log-in
field of the “Research & Related Senior/Key Person Profile” component must
contain the PD/PI’s assigned eRA Commons User ID). Agency-specific
instructions for such fields are clearly identified in the Application Guide.
For additional information, see “Frequently Asked Questions – Application
Guide, Electronic
Submission of Grant Applications.”

The SF424 (R&R)
application has several components. Some components are required, others are optional.
The forms package associated with this FOA in Grants.gov/APPLYincludes all applicable components, required and optional. A completed
application in response to this FOA includes the data in the following
components:

Proposed research should provide special opportunities
for furthering research programs through the use of unusual talent, resources,
populations, or environmental conditions in other countries that are not
readily available in the United States (U.S.) or that augment existing U.S. resources.

SPECIAL INSTRUCTIONS

Applications with
Multiple PDs/PIs

When
multiple PDs/PIs are proposed, NIH requires one PD/PI to be designated as the
"Contact” PI, who will be responsible for all communication between the
PDs/PIs and the NIH, for assembling the application materials outlined below,
and for coordinating progress reports for the project. The contact PD/PI must
meet all eligibility requirements for PD/PI status in the same way as other
PDs/PIs, but has no other special roles or responsibilities within the project
team beyond those mentioned above.

Information
for the Contact PD/PI should be entered in item 15 of the SF424 (R&R) Cover
component. All other PDs/PIs should be listed in the Research &
Related Senior/Key Person component and assigned the project role of “PD/PI.” Please
remember that all PDs/PIs must be registered in the eRA Commons prior to
application submission. The Commons ID of each PD/PI must be included in the
“Credential” field of the Research & Related Senior/Key Person
component. Failure to include this data field will cause the application
to be rejected.

All projects
proposing Multiple PDs/PIs will be required to include a new section describing
the leadership plan approach for
the proposed project.

Multiple
PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new
section of the research plan, entitled “Multiple PD/PI Leadership Plan”
[Section 14 of the Research Plan Component in the SF424 (R&R)], must be
included. A rationale for choosing a multiple PD/PI approach should be described.
The governance and organizational structure of the leadership team and the
research project should be described, and should include communication plans,
process for making decisions on scientific direction, and procedures for
resolving conflicts. The roles and administrative, technical, and
scientific responsibilities for the project or program should be delineated for
the PDs/PIs and other collaborators.

If
budget allocation is planned, the distribution of resources to specific
components of the project or the individual PDs/PIs should be delineated in the
Leadership Plan. In the event of an award, the requested allocations may be
reflected in a footnote on the Notice of Award (NoA).

Applications Involving a
Single Institution

When all PDs/PIs are within
a single institution, follow the instructions contained in the SF424 (R&R)
Application Guide.

Applications Involving
Multiple Institutions

When
multiple institutions are involved, one institution must be designated as the
prime institution and funding for the other institution(s) must be requested
via a subcontract to be administered by the prime institution. When submitting
a detailed budget, the prime institution should submit its budget using the
Research & Related Budget component. All other institutions should
have their individual budgets attached separately to the Research & Related
Subaward Budget Attachment(s) Form. See Section 4.8 of the SF424 (R&R)
Application Guide for further instruction regarding the use of the subaward budget
form.

When
submitting a modular budget, the prime institution completes the PHS398 Modular
Budget component only. Information concerning the consortium/subcontract
budget is provided in the budget justification. Separate budgets for each
consortium/subcontract grantee are not required when using the Modular budget
format. See Section 5.4 of the Application Guide for further instruction
regarding the use of the PHS398 Modular Budget component.

Prospective
applicants are asked to submit a letter of intent that includes the following
information:

Descriptive title of proposed research.

Name, address, and telephone number of the
PD(s)/PI(s).

Names of other key personnel.

Participating institutions.

Number and title of this funding opportunity.

Although
a letter of intent is not required, is not binding, and does not enter into the
review of a subsequent application, the information that it contains allows IC
staff to estimate the potential review workload and plan the review.

In order to expedite the
review, applicants are requested to notify the NIDA Referral
Office by email vchiu@nida.nih.govwhen the application has been
submitted. Please include the FOA number and title, PD/PI name, and
title of the application.

3.C.
Application Processing

Applications may be submitted on or after the opening date and must be
successfully received by Grants.gov no later than 5:00 p.m. local time (of the applicant
institution/organization) on the application due date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the due date(s)
and time, the application may be delayed in the review process or not reviewed.

Once an application package has been successfully
submitted through Grants.gov, any errors have been addressed, and the assembled
application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing
Official (AOR/SO) have two weekdays (Monday – Friday, excluding Federal
holidays) to view the application image to determine if any further action is
necessary.

If everything is acceptable, no
further action is necessary. The application will automatically
move forward to the Division of Receipt and Referral in the Center for
Scientific Review for processing after two weekdays, excluding Federal holidays.

Prior to the submission deadline, the
AOR/SO can “Reject” the assembled application and submit a
changed/corrected application within the two-day viewing window. This
option should be used if it is determined that some part of the
application was lost or did not transfer correctly during the submission
process, the AOR/SO will have the option to “Reject” the application and
submit a Changed/Corrected application. In
these cases, please contact the eRA Help Desk to ensure that the issues
are addressed and corrected. Once rejected, applicants should follow the
instructions for correcting errors in Section 2.12, including the
requirement for cover letters on late applications. The
“Reject” feature should also be used if you determine that warnings are
applicable to your application and need to be addressed now. Remember,
warnings do not stop further application processing. If an application
submission results in warnings (but no errors), it will automatically move
forward after two business days if no action is taken. Some warnings may
need to be addressed later in the process.

If
the two-day window falls after the submission deadline, the AOR/SO will have
the option to “Reject” the application if, due to an eRA Commons or Grants.gov
system issue, the application does not correctly reflect the submitted
application package (e.g., some part of the application was lost or didn’t
transfer correctly during the submission process). The AOR/SO should first
contact the eRA Commons Helpdesk to confirm the system error, document the issue, and determine the best course
of action. NIH will not penalize the applicant for an eRA Commons or Grants.gov system issue.

If
the AOR/SO chooses to “Reject” the image after the submission deadline for a
reason other than an eRA Commons or Grants.gov system failure, a
changed/corrected application still can be submitted, but it will be subject to
the NIH
late policy guidelines and may not be accepted. The reason for this delay
should be explained in the cover letter attachment.

Both
the AOR/SO and PD/PI will receive e-mail notifications when the application is
rejected or the application automatically moves forward in the process after
two days.

Upon receipt, applications will be evaluated for
completeness by the CSR and responsiveness by the IC. Incomplete and
non-responsive applications will not be reviewed.

There
will be an acknowledgement of receipt of applications from Grants.gov and the Commons. The submitting AOR/SO
receives the Grants.gov acknowledgments. The AOR/SO and the PI receive Commons acknowledgments. Information related to the assignment of an application to a Scientific
Review Group is also in the Commons.

Note: Since email can be
unreliable, it is the responsibility of the applicant to check periodically on
the application status in the Commons.

The
NIH will not accept any application in response to this funding opportunity
that is essentially the same as one currently pending initial review, unless
the applicant withdraws the pending application. However, when a previously
unfunded application, originally submitted as an investigator-initiated
application, is to be submitted in response to a funding opportunity, it is to
be prepared as a NEW application. That is, the application for the funding
opportunity must not include an “Introduction” describing the changes and
improvements made, and the text must not be marked to indicate the changes from
the previous unfunded version of the application.

All NIH awards are
subject to the terms and conditions, cost principles, and other considerations
described in the NIH Grants Policy Statement.

Pre-award costs are allowable. A grantee may, at its
own risk and without NIH prior approval, incur obligations and expenditures to
cover costs up to 90 days before the beginning date of the initial budget
period of a new or competing renewal award if such costs: 1) are necessary to
conduct the project, and 2) would be allowable under the grant, if awarded,
without NIH prior approval. If specific expenditures would otherwise require
prior approval, the grantee must obtain NIH approval before incurring the cost.
NIH prior approval is required for any costs to be incurred more than 90 days
before the beginning date of the initial budget period of a new or competing
renewal award.

The incurrence of pre-award costs in anticipation of a
competing or non-competing award imposes no obligation on NIH either to make
the award or to increase the amount of the approved budget if an award is made
for less than the amount anticipated and is inadequate to cover the pre-award
costs incurred. NIH expects the grantee to be fully aware that pre-award costs
result in borrowing against future support and that such borrowing must not
impair the grantee's ability to accomplish the project objectives in the
approved time frame or in any way adversely affect the conduct of the project
(see theNIH
Grants Policy Statement).

The
applicant organization must include its DUNS number in its Organization Profile
in the eRA Commons. This DUNS number must match the DUNS number provided at CCR
registration with Grants.gov. For
additional information, see “Frequently Asked Questions – Application Guide, Electronic
Submission of Grant Applications.”

PHS398
Research Plan Component Sections

Page
limitations of the PHS398 Research Plan component must be followed as outlined
in the SF424 (R&R) Application Guide. While each section of the Research
Plan component needs to be uploaded separately as a PDF attachment, applicants
are encouraged to construct the Research Plan component as a single document,
separating sections into distinct PDF attachments just before uploading the
files. This approach will enable applicants to better monitor formatting
requirements such as page limits. All attachments must be provided to NIH in
PDF format, filenames must be included with no spaces or special characters,
and a .pdf extension must be used.

All
application instructions outlined in the SF424 (R&R) Application Guide are
to be followed, incorporating "Just-in-Time" information concepts,
and with the following additional requirements for R03 applications:

Items 2-5
of the PHS398 Research Plan component of the R03 application may not
exceed 10 pages, including tables, graphs, figures, diagrams, and charts.

Preliminary
data are not required but may be included if available.

R03
Appendix materials may include only pre-printed questionnaires or surveys.
No publications or figures are allowed in the Appendix.

Do not use the Appendix to circumvent the page limitations of
the Research Plan component. An application that does not comply with the
required page limitations may be delayed in the review process.

Resource Sharing
Plan(s)

NIH considers
the sharing of unique research resources developed through NIH-sponsored
research an important means to enhance the value and further the advancement of
the research. When resources have been developed with NIH funds and the
associated research findings published or provided to NIH, it is important that
they be made readily available for research purposes to qualified individuals
within the scientific community. If the final
data/resources are not amenable to sharing, this must be explained in the
Resource Sharing section of the application (see http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.)

(b) Sharing Model Organisms: Regardless of
the amount requested, all applications where the development of model organisms
is anticipated are expectedto include a description of a
specific plan for sharing and distributing unique model organisms and related
resources or state appropriate reasons why such sharing is restricted or not
possible (see Sharing
Model Organisms Policy, and NOT-OD-04-042.)

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount
requested, applicants seeking funding for a genome-wide association
study are expected to provide a plan for submission of GWAS data to the
NIH-designatedGWAS data repository, or provide an appropriate
explanation why submission to the repository is not possible. A genome-wide
association study is defined as any study of genetic variation across the
entire genome that is designed to identify genetic associations with observable
traits (e.g., blood pressure or weight) or the presence or absence of a disease
or condition. For further information see Policy for Sharing of Data
Obtained in NIH Supported or Conducted Genome-Wide Association Studies (go to NOT-OD-07-088, and http://grants.nih.gov/grants/gwas/.)

Applicants are expected to
document access to existing DNA sequence and genotype data, and if appropriate,
to phenotype data and possibly exposure data. Applicants should describe all
relevant phenotypic, genotypic, and environmental
exposure measures from the study.

Applicants are expected to provide
a plan to share any computational tools and methods with the scientific
community in a timely manner, and should address any concerns regarding
intellectual property. Any application that does not
include this information will be considered non-responsive.

Applicants should include funds in
their second year budget to attend one meeting for this program in the Bethesda, MD, area.

Applications that include the
recruitment of human subjects, collection of
biological samples, large-scale sequencing, and secondary data analysis will be
considered non-responsive and returned to the applicant.

If selected, NIH intramural
scientists will participate in GEI programs as Principal Investigators in accord with the Terms and Conditions of Award
provided in this FOA.

NIH encourages the development of
tools and resources based on data that are broadly available to the research
community.

The NIH expects that all
GEI-supported data, results, methods, tools, and
resources will remain freely available, without licensing requirements, for
uses such as, but not limited to, methods and tools for identifying markers
that can be used for new potential drug targets, therapeutics and diagnostics.
The intent is to discourage the use of patents that
would prevent use or block access to any methods or tools developed with GEI
support. The NIH encourages broad use of methods and tools that are consistent
with a responsible approach to management of intellectual
property derived from downstream discoveries as outlined in NIH’s Best
Practices for Licensing of Genomic Inventions and the NIH Research Tools Policy
(http://grants.nih.gov/grants/intell-property_64FR72090.pdf).

Intellectual property will be
managed in accord with established policy of the NIH in compliance with
Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions
developed in NIH facilities are NIH property unless
NIH waives its rights.

Foreign Applications
(Non-Domestic [non-U.S.] Entities)

Indicate how the proposed project has specific
relevance to the mission and objectives of the NIH/IC and has the potential for
significantly advancing the health sciences in the United States.

Section V. Application Review Information

1.
Criteria

Only
the review criteria described below will be considered in the review process.

2. Review and
Selection Process

Applications that are
complete and responsive to this FOA will be evaluated for scientific and technical merit by an appropriate peer review
group convened by NIDA and in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/),
using the review criteria stated below.

As
part of the scientific peer review, all applications will:

Undergo a
selection process in which only those applications deemed to have the
highest scientific and technical merit, generally the top half of applications
under review, will be discussed and assigned a priority score;

Receive a
written critique; and

Receive a second level of review by NIDA
Council

Applications
submitted in response to this FOA will compete for available funds with all
other recommended applications submitted in response to this FOA. The following will be
considered in making funding decisions:

Scientific
merit of the proposed project as determined by peer review.

Availability
of funds.

Relevance
of the proposed project to program priorities.

Compliance with resource sharing policies

Programmatic balance among diseases

Synergy with other funded projects

The goals of NIH
supported research are to advance our understanding of biological systems, to
improve the control of disease, and to enhance health. In their written
critiques, reviewers will be asked to comment on each of the following criteria
in order to judge the likelihood that the proposed research will have a
substantial impact on the pursuit of these goals. Each of these criteria will
be addressed and considered in assigning the overall score, and weighted as
appropriate for each application. Note that an application does not need to be
strong in all categories to be judged likely to have major scientific impact
and thus deserve a meritorious priority score. For example, an investigator may
propose to carry out important work that by its nature is not innovative but is
essential to move a field forward.

Significance:Does this study address an important problem? If
the aims of the application are achieved, how will scientific knowledge or
clinical practice be advanced? What will be the effect of these studies on the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field? Does the application address the goals and objectives
outlined in the FOA?

Approach:Are the
conceptual or clinical framework, design, methods, and analyses adequately
developed, well integrated, well reasoned, and appropriate to the aims of the
project? Does the applicant acknowledge potential problem areas and consider
alternative tactics? For applications designating multiple PDs/PIs, is the
leadership approach, including the designated roles and responsibilities,
governance, and organizational structure, consistent with and justified by the
aims of the project and the expertise of each of the PDs/PIs?Does the
approach proposed provide the best chance for success at addressing the
hypothesis stated? Does the approach include appropriate gender/ethnic considerations? Is there population diversity of gene
variant(s) selected, or conditions disproportionately affecting
underrepresented minorities? Will the data be of high quality and the proposed
methods straight-forward? Did the applicant adequately justify the selection of the gene variant(s) to be characterized, and include the following: (1)
Summary of the study (e.g. GWAS, candidate gene, QTL) identifying the gene
variant, as well as the replication or validation data to support its
prioritization for further functional analysis; (2) A justification of the
functional characterization approach as well as a justification of the
environmental factor(s) proposed to examine G x E, if applicable; (3)
Sensitivity of the functional measurement (will you be successful in detecting
a functional change); and (4) Potential analytic interpretations of the
functional effect and alternative corrections in establishing mechanism (e.g.
there may be redundancies and compensatory mechanisms built into the system, which
may need to be taken into account).

Innovation: Is
the project original and innovative? For example: Does the project challenge existing
paradigms or clinical practice; address an innovative hypothesis or critical
barrier to progress in the field? Does the project develop or employ novel
concepts, approaches, methodologies, tools, or technologies for this area?

Investigators:Are the PD(s)/PI(s) and other key personnel appropriately
trained and well suited to carry out this work? Is the work proposed
appropriate to the experience level of the principal investigator and other
researchers? Do(es) the PD(s)/PI(s) and investigative team bring complementary
and integrated expertise to the project (if applicable)?

Environment: Do(es) the
scientific environment(s) in which the work will be done contribute to the
probability of success? Do the proposed studies benefit from unique features of
the scientific environment, or subject populations, or employ useful
collaborative arrangements? Is there evidence of institutional support?

2.A.
Additional Review Criteria

In addition to
the above criteria, the following items will continue to be considered in the
determination of scientific merit and the rating:

Protection
of Human Subjects from Research Risk: The involvement of human
subjects and protections from research risk relating to their participation in
the proposed research will be assessed. See the “Human Subjects Sections”
of the PHS398 Research Plan component of the SF424 (R&R).

Inclusion of Women, Minorities and Children in Research: The adequacy of
plans to include subjects from both genders, all racial and ethnic groups (and
subgroups), and children as appropriate for the scientific goals of the
research will be assessed. Plans for the recruitment and retention of subjects
will also be evaluated. See the “Human Subjects Sections” of the PHS398
Research Plan component of the SF424 (R&R)

Care and Use of Vertebrate Animals in Research: If vertebrate animals
are to be used in the project, the adequacy of the plans for their care and use
will be assessed. See the “Other Research Plan Sections” of the PHS398 Research
Plan component of the SF424 (R&R).

Biohazards: If materials or procedures are proposed that are potentially
hazardous to research personnel and/or the environment, determine if the
proposed protection is adequate.

2.B. Additional Review Considerations

Budget and
Period of Support: The reasonableness of the proposed budget and the
appropriateness of the requested period of support in relation to the proposed
research may be assessed by the reviewers. The priority score should not be
affected by the evaluation of the budget.

Applications from Foreign Organizations: Whether the project presents special opportunities
for furthering research programs through the use of unusual talent, resources,
populations, or environmental conditions in other countries that are not
readily available in the United States or that augment existing U.S. resources will be assessed.

2.C. Resource Sharing
Plan(s)

When relevant, reviewers will be instructed to comment
on the reasonableness of the following Resource Sharing Plans, or the rationale
for not sharing the following types of resources. However, reviewers will not
factor the proposed resource sharing plan(s) into the determination of
scientific merit or priority score, unless noted otherwise in the FOA. Program
staff within the IC will be responsible for monitoring the resource sharing.

A formal notification in the form of a Notice of Award
(NoA) will be provided to the applicant organization. The NoA signed by the
grants management officer is the authorizing document. Once all administrative
and programmatic issues have been resolved, the NoA will be generated via email
notification from the awarding component to the grantee business official.

Selection of an application for award is not an
authorization to begin performance. Any costs incurred before receipt of the
NoA are at the recipient's risk. These costs may be reimbursed only to the
extent considered allowable pre-award costs. See Section
IV.5., “Funding Restrictions.”

A final progress
report, invention statement, and Financial Status Report are required when an
award is relinquished when a recipient changes institutions or when an award is
terminated.

Section VII. Agency Contacts

We
encourage your inquiries concerning this funding opportunity and welcome the
opportunity to answer questions from potential applicants. Inquiries may fall
into three areas: scientific/research (program), peer review, and financial or
grants management issues:

Human Subjects
Protection:Federal regulations (45 CFR 46) require that
applications and proposals involving human subjects must be evaluated with
reference to the risks to the subjects, the adequacy of protection against
these risks, the potential benefits of the research to the subjects and others,
and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety
Monitoring Plan:Data and safety monitoring is required for all types
of clinical trials, including physiologic toxicity and dose-finding studies
(Phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative
trials (Phase III). Monitoring should be commensurate with risk. The
establishment of data and safety monitoring boards (DSMBs) is required for
multi-site clinical trials involving interventions that entail potential risks
to the participants (“NIH Policy for Data and Safety Monitoring,” NIH Guide
for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:Investigators submitting an NIH application seeking
$500,000 or more in direct costs in any single year are expected to include a
plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).Investigators should seek guidance from their
institutions, on issues related to institutional policies and local
institutional review board (IRB) rules, as well as local, State and Federal
laws and regulations, including the Privacy Rule. Reviewers will consider the
data sharing plan but will not factor the plan into the determination of the
scientific merit or the priority score.

Policy for Genome-Wide
Association Studies (GWAS):NIH is interested in advancing genome-wide association
studies (GWAS) to identify common genetic factors that influence health and
disease through a centralized GWAS data repository. For the purposes of this
policy, a genome-wide association study is defined as any study of genetic
variation across the entire human genome that is designed to identify genetic
associations with observable traits (such as blood pressure or weight), or the
presence or absence of a disease or condition. All applications, regardless of
the amount requested, proposing a genome-wide association study are expected to
provide a plan for submission of GWAS data to the NIH-designated GWAS data
repository, or provide an appropriate explanation why submission to the
repository is not possible. Data repository management (submission and access)
is governed by the Policy for Sharing of Data Obtained in NIH Supported or
Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088.
For additional information, see http://grants.nih.gov/grants/gwas/.

Sharing of Model Organisms:NIH is committed to support efforts that encourage sharing
of important research resources including the sharing of model organisms for
biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm).
At the same time the NIH recognizes the rights of grantees and contractors to
elect and retain title to subject inventions developed with Federal funding
pursuant to the Bayh-Dole Act (see the NIH
Grants Policy Statement. Beginning October 1, 2004, all investigators
submitting an NIH application or contract proposal are expected to include in
the application/proposal a description of a specific plan for sharing and distributing
unique model organism research resources generated using NIH funding or state
why such sharing is restricted or not possible. This will permit other
researchers to benefit from the resources developed with public funding. The
inclusion of a model organism sharing plan is not subject to a cost threshold
in any year and is expected to be included in all applications where the
development of model organisms is anticipated.

Access to Research Data through the Freedom of
Information Act:The Office of Management and Budget (OMB) Circular
A-110 has been revised to provide access to research data through the Freedom
of Information Act (FOIA) under some circumstances. Data that are: (1) first
produced in a project that is supported in whole or in part with Federal funds;
and (2) cited publicly and officially by a Federal agency in support of an
action that has the force and effect of law (i.e., a regulation) may be
accessed through FOIA. It is important for applicants to understand the basic
scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this funding opportunity in a
public archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application should
include a description of the archiving plan in the study design and include
information about this in the budget justification section of the application.
In addition, applicants should think about how to structure informed consent
statements and other human subjects procedures given the potential for wider
use of data collected under this award.

Inclusion of Women And Minorities in Clinical Research:It is the policy of the NIH that women and members of
minority groups and their sub-populations must be included in all NIH-supported
clinical research projects unless a clear and compelling justification is
provided indicating that inclusion is inappropriate with respect to the health
of the subjects or the purpose of the research. This policy results from the
NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All
investigators proposing clinical research should read the "NIH Guidelines
for Inclusion of Women and Minorities as Subjects in Clinical Research” (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical
research; updated racial and ethnic categories in compliance with the new OMB
standards; clarification of language governing NIH-defined Phase III clinical
trials consistent with the SF424 (R&R) application; and updated roles and
responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: a) all
applications or proposals and/or protocols must provide a description of plans
to conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable; and b)
investigators must report annual accrual and progress in conducting analyses,
as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:The NIH maintains a policy that children (i.e.,
individuals under the age of 21) must be included in all clinical research,
conducted or supported by the NIH, unless there are scientific and ethical
reasons not to include them. All investigators proposing research involving
human subjects should read the "NIH Policy and Guidelines" on the
inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:NIH policy requires education on the protection of
human subject participants for all investigators submitting NIH applications
for research involving human subjects and individuals designated as key
personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):Criteria for Federal funding of research on hESCs can
be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.
Only research using hESC lines that are registered in the NIH Human Embryonic
Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov/). It is the responsibility
of the applicant to provide in the project description and elsewhere in the
application as appropriate, the official NIH identifier(s) for the hESC line(s)
to be used in the proposed research. Applications that do not provide this
information will be returned without review.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy, investigators
funded by the NIH must submit or have submitted for them to the National
Library of Medicine’s PubMed Central (see http://www.pubmedcentral.nih.gov/), an
electronic version of their final, peer-reviewed manuscripts upon acceptance
for publication, to be made publicly available no later than 12 months after
the official date of publication. The NIH Public Access Policy is
available at (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html).For more information, see the Public
Access webpage at http://publicaccess.nih.gov/.

Standards for Privacy of Individually Identifiable Health Information:The Department of Health and Human Services (HHS)
issued final modification to the "Standards for Privacy of Individually
Identifiable Health Information", the "Privacy Rule", on August
14, 2002. The Privacy Rule is a federal regulation under the Health Insurance
Portability and Accountability Act (HIPAA) of 1996 that governs the protection
of individually identifiable health information, and is administered and
enforced by the HHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of
the Privacy Rule reside with the researcher and his/her institution. The OCR
website (http://www.hhs.gov/ocr/)
provides information on the Privacy Rule, including a complete Regulation Text
and a set of decision tools on "Am I a covered entity?" Information
on the impact of the HIPAA Privacy Rule on NIH processes involving the review,
funding, and progress monitoring of grants, cooperative agreements, and research
contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs
in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding
must be self-contained within specified page limitations. For publications
listed in the appendix and/or Progress report, Internet addresses (URLs) or
PubMed Central (PMC) submission identification numbers must be used for
publicly accessible on-line journal articles. Publicly accessible on-line
journal articles or PMC articles/manuscripts accepted for publication that are
directly relevant to the project may be included only as URLs or PMC
submission identification numbers accompanying the full reference in either
the Bibliography & References Cited section, the Progress Report
Publication List section, or the Biographical Sketch section of the NIH grant
application. A URL or PMC submission identification number citation may be repeated
in each of these sections as appropriate. There is no limit to the number of
URLs or PMC submission identification numbers that can be cited.

Healthy People 2010:The Public Health Service (PHS) is committed to
achieving the health promotion and disease prevention objectives of
"Healthy People 2010," a PHS-led national activity for setting
priority areas. This FOA is related to one or more of the priority areas.
Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:This program is
described in the Catalog
of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems
Agency review. Awards are made under the authorization of Sections 301 and 405
of the Public Health Service Act as amended (42 USC 241 and 284) and under
Federal Regulations 42 CFR Part 52 and 45 CFR Parts
74 and 92. All awards are subject to the terms and conditions, cost principles,
and other considerations described in the NIH Grants
Policy Statement.

The PHS strongly encourages all grant recipients to
provide a smoke-free workplace and discourage the use of all tobacco products.
In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits
smoking in certain facilities (or in some cases, any portion of a facility) in
which regular or routine education, library, day care, health care, or early
childhood development services are provided to children. This is consistent
with the PHS mission to protect and advance the physical and mental health of
the American people.

Loan Repayment Programs:NIH encourages applications for educational loan
repayment from qualified health professionals who have made a commitment to
pursue a research career involving clinical, pediatric, contraception,
infertility, and health disparities related areas. The LRP is an important
component of NIH's efforts to recruit and retain the next generation of
researchers by providing the means for developing a research career unfettered
by the burden of student loan debt. Note that an NIH grant is not required for
eligibility and concurrent career award and LRP applications are encouraged.
The periods of career award and LRP award may overlap providing the LRP
recipient with the required commitment of time and effort, as LRP awardees must
commit at least 50% of their time (at least 20 hours per week based on a 40
hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov/.